PDE5A Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking through a Noncanonical cGMP-Dependent Pathway

Abstract Noncanonical metabolic functions of signaling molecules contribute to cancer plasticity and metastatic progression. In this study, we demonstrated that phosphodiesterase type 5A (PDE5A) inhibitors, including sildenafil (Sild; Viagra), induced lysosomal cholesterol accumulation across multiple mouse and human cancer models, reducing cholesterol bioavailability and impairing cancer cell migration and metastasis. Cancer cells exhibited heightened sensitivity due to reduced lysosomal gene expression, rendering them particularly vulnerable to disrupted cholesterol trafficking. Mechanistically, elevated guanosine 3′,5′-cyclic monophosphate (cGMP) bound the lysosomal cholesterol transporter NPC1, impairing cholesterol export and phenocopying Niemann–Pick type C pathology. The resulting cholesterol depletion disrupted membrane lipid rafts and mitochondrial bioenergetics, thereby limiting metastatic capacity and triggering compensatory sterol regulatory element–binding protein 2 (SREBP2) activation with increased cholesterol synthesis. Combining Sild with statins yields additive antimetastatic effects by concurrently blocking lysosomal cholesterol export and cholesterol biosynthesis. Consistently, analysis of digital health records demonstrated significantly improved survival among Sild users, with a dose-dependent additive benefit observed when combined with statins. Together, these findings identify increasing cGMP levels through PDE5A inhibition as a potential strategy to restrict metastasis and offer a potential mechanistic basis for the beneficial effects of Sild. Significance: PDE5A inhibition is linked to lysosomal cholesterol trafficking and reduced metastasis via cGMP-mediated disruption of NPC1 export, providing insights into how non-oncologic drugs and host–tumor metabolism influence progression and outcomes.